Abstract
Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcpz and HIV-1 are pathogenic in their respective hosts, while the phenotype of their SIVgsn/mus/mon ancestors is unknown. However, two well-studied SIV infected natural hosts, sooty mangabeys (SMs) and African green monkeys (AGMs), typically remain healthy despite high viral loads; these species express low levels of the canonical coreceptor CCR5, and recent work shows that CXCR6 is a major coreceptor for SIV in these hosts. It is not known what coreceptors were used by the precursors of SIVcpz, whether coreceptor use changed during emergence of the SIVcpz/HIV-1 lineage, and what T cell subsets express CXCR6 in natural hosts. Using species-matched coreceptors and CD4, we show here that SIVcpz uses only CCR5 for entry and, like HIV-1, cannot use CXCR6. In contrast, SIVmus efficiently uses both CXCR6 and CCR5. Coreceptor selectivity was determined by Env, with CXCR6 use abrogated by Pro326 in the V3 crown, which is absent in monkey SIVs but highly conserved in SIVcpz/HIV-1. To characterize which cells express CXCR6, we generated a novel antibody that recognizes CXCR6 of multiple primate species. Testing lymphocytes from SM, the best-studied natural host, we found that CXCR6 is restricted to CD4+ effector memory cells, and is expressed by a sub-population distinct from those expressing CCR5. Thus, efficient CXCR6 use, previously identified in SM and AGM infection, also characterizes a member of the SIV lineage that gave rise to SIVcpz/HIV-1. Loss of CXCR6 usage by SIVcpz may have altered its cell tropism, shifting virus from CXCR6-expressing cells that may support replication without disrupting immune function or homeostasis, towards CCR5-expressing cells with pathogenic consequences.
Highlights
Pandemic HIV-1 resulted from the cross-species transmission of SIVcpz, which infects chimpanzees (Pan troglodytes), into humans [1, 2]
We asked which entry coreceptors are used by SIVcpz, the HIV-1 precursor that is pathogenic in chimpanzees, and by SIVmus, a member of the monkey SIV lineage that contributed the env gene of SIVcpz
We examined CXCR6 expression on sooty mangabey CD4+ T cells, and found it is present on a subset of differentiated memory T cells distinct from cells expressing CCR5
Summary
Pandemic HIV-1 resulted from the cross-species transmission of SIVcpz, which infects chimpanzees (Pan troglodytes), into humans [1, 2]. SIVcpz itself emerged in chimpanzees following the cross-species transmission and recombination of SIVs infecting monkeys on which chimpanzees prey [3, 4]. The 5’ half of SIVcpz, which encodes gag and pol, is derived mainly from SIVrcm that infects red-capped mangabeys (RCM, Cercocebus torquatus) [3, 5]. RCMs, GSNs, MUSs and MONs are among more than forty African primate species known to be naturally infected with species-specific strains of SIV [8]. SIVmac infection of rhesus (RM, Macaca mulatta) and other macaque species, which serves as the primary animal model for AIDS, is the result of cross-species transmission of SIVsmm from SM. The lack of pathogenicity in SMs and AGMs is believed to be the product of millions of years of virus-host coevolution, while the more recent introduction of HIV-1, SIVcpz and SIVmac into a “nonnatural” host is believed to underlie, at least in part, the pathogenic outcomes of these infections [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
